DESCRIPTION:(Adapted from Investigator's abstract): The Diabetes Prevention Trial (DPT-1) was formed to test whether antigen specific therapies can prevent type 1 diabetes in persons at increased-risk for the disease. The trial involves autoantibody, genetic, and metabolic screening of non-diabetic relatives of type I diabetes patients to determine disease-risk, followed by randomized assignment of high-risk individuals to a daily prophylactic dose of subcutaneous insulin/annual intensive intravenous insulin therapy and intermediate-risk persons to daily oral treatment (placebo or oral insulin). Both treatment arms have untreated control groups subject to identical follow-up analyses. Examination of changes in the immune response, including those against insulin, may yield valuable information as to the mechanism of (presumed) disease prevention. While such studies are (unfortunately) not part of the formal DPT-1 trial, we have received separate NIH support (R0l Al39250) to perform such investigations. This proposal represents an important continuation as well as an expansion of these studies aimed at addressing the question as to how insulin therapy effects the autoimmune response. Analysis of both therapy responders and non-responders may indicate: 1) a mechanism whereby subsequent trials may be improved, 2) identify those with the best chance of a positive therapeutic response, or 3) provide a more refined assessment of diabetes risk based on immunologic phenotypes. Finally, examination of high-risk individuals from the untreated parenteral arm, or placebo treated subjects, will further our understanding of the natural history of the cellular immune response in the prediabetic period. This proposal tests two hypotheses: 1) that CD1d-restricted T cells interact with dendritic cells (DC)and that this axis is dysfunctional in at-risk pre-diabetic individuals, and 2) that the development of disease correlates with parameters of T cell autoimmunity wherein Th1-like immunities against an expanded repertoire of beta cell antigens (afforded in-part by the aforementioned dysfunctions occurs in association with diminished Th2-like responses. These hypotheses will be tested through performance of four specific aims including: 1) monitoring T cell responses (blastogeneis, cytokine production) to islet cell antigens including insulin, 2) analysis of DC subsets and antigen presenting cell function, 3) determining the frequency of circulating CD1d-restricted T cells, and 4) analysis of the effector functions of CD1d-restricted T cell clones. In sum, our purpose is to delineate the mechanism of disease prevention provided by prophylactic insulin therapy and to further understand the natural history of cellular immune responses in the prediabetic period.